1. Field of the Invention
The present invention relates to a novel preparation of (S)-(+)-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine, by using chiral methylhydroxylaminopropanol derivative as an intermediate.
2. Description of Related Art
(S)-(+)-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine (Duloxetine®) is an antidepressant drug developed by Eli Lilly and Company, Inc. Various methods have been reported to prepare Duloxetine®. For example, U.S. Pat. No. 5,023,269 discloses a process as shown in the following scheme:
In this example, 2-acetylthiophene is used as the starting material for reacting with formaldehyde and dimethylamine to form a Mannich product namely 3-dimethylamino-1-(2-thienyl)propan-1-one. A hydride reduction is performed on this propanone to form corresponding 3-dimethylamino-1-(2-thienyl)propan-1-ol. The resulting propanol is then reacted with fluoronaphthalene to form N,N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine. Subsequently, racemic Duloxetine® is obtained by demethylation of this propylamine. In this process, the yield of demethylation is very low, about 41%. In addition, Duloxetine® produced via this route is racemic. Resolution is therefore needed to obtain chiral Duloxetine which renders this process less competitive.